A focused screening approach is proposed to identify small molecules that are able to specifically bind to the blood serum protein transthyretin (TTR), and inhibit its assembly into amyloid (insoluble protein deposits implicated in many diseases). This will be accomplished in two linked steps. First, the available structure-activity data for TTR binding will he used to design series of compounds that are likely to bind tightly to TTR. Second, the compounds will be evaluated for their ability to inhibit amyloid formation and the actual binding parameters will be measured. The most promising inhibitors will be crystallized as complexes with TTR to determine their mode of binding. The information thus gained will be re-applied to the design of more compounds for testing, and the process will be repeated. A few iterations of this process should yield compounds that inhibit TTR amyloid formation actively enough to serve as possible drugs for the treatment of the TTR associated diseases familial amyloidotic polyneuropathy and senile systemic amyloidosis.